PMID- 32057709
OWN - NLM
STAT- MEDLINE
DCOM- 20210618
LR  - 20220531
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 32
DP  - 2020 May
TI  - Tsg101 positively regulates P62-Keap1-Nrf2 pathway to protect hearts against 
      oxidative damage.
PG  - 101453
LID - S2213-2317(20)30002-1 [pii]
LID - 10.1016/j.redox.2020.101453 [doi]
LID - 101453
AB  - Currently, most antioxidants do not show any favorable clinical outcomes in 
      reducing myocardial ischemia-reperfusion (I/R) injury, suggesting an urgent need 
      for exploring a new regulator of redox homeostasis in I/R hearts. Here, using 
      heart-specific transgenic (TG) and knockdown (KD) mouse models, tumor 
      susceptibility gene 101 (Tsg101) is defined as a novel cardiac-protector against 
      I/R-triggered oxidative stress. RNA sequencing and bioinformatics data 
      surprisingly reveal that most upregulated genes in Tsg101-TG hearts are 
      transcribed by Nrf2. Accordingly, pharmacological inhibition of Nrf2 offsets 
      Tsg101-elicited cardio-protection. Mechanistically, Tsg101 interacts with 
      SQSTM1/p62 through its PRR domain, and promotes p62 aggregation, leading to 
      recruitment of Keap1 for degradation by autophagosomes and release of Nrf2 to the 
      nucleus. Furthermore, knockout of p62 abrogates Tsg101-induced cardio-protective 
      effects during I/R. Hence, our findings uncover a previously unrecognized role of 
      Tsg101 in the regulation of p62/Keap1/Nrf2 signaling cascades and provide a new 
      strategy for the treatment of ischemic heart disease.
CI  - Copyright (c) 2020 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Deng, Shan
AU  - Deng S
AD  - Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, Hubei, 430022, China; Department of 
      Pharmacology and Systems Physiology, University of Cincinnati College of 
      Medicine, Cincinnati, OH, 45267, USA; Clinical Center for Human Genomic Research, 
      Union Hospital, Tongji Medical College, Huazhong University of Science and 
      Technology, Wuhan, Hubei, 430022, China.
FAU - Essandoh, Kobina
AU  - Essandoh K
AD  - Department of Pharmacology and Systems Physiology, University of Cincinnati 
      College of Medicine, Cincinnati, OH, 45267, USA.
FAU - Wang, Xiaohong
AU  - Wang X
AD  - Department of Pharmacology and Systems Physiology, University of Cincinnati 
      College of Medicine, Cincinnati, OH, 45267, USA.
FAU - Li, Yutian
AU  - Li Y
AD  - Department of Pharmacology and Systems Physiology, University of Cincinnati 
      College of Medicine, Cincinnati, OH, 45267, USA.
FAU - Huang, Wei
AU  - Huang W
AD  - Department of Pathology and Laboratory Medicine, University of Cincinnati College 
      of Medicine, Cincinnati, OH, 45267, USA.
FAU - Chen, Jing
AU  - Chen J
AD  - Division of Biomedical Informatics, Cincinnati Children's Hospital Medical 
      Center, Cincinnati, OH, 45229, USA.
FAU - Peng, Jiangtong
AU  - Peng J
AD  - Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, Hubei, 430022, China; Clinical 
      Center for Human Genomic Research, Union Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
FAU - Jiang, Ding-Sheng
AU  - Jiang DS
AD  - Division of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical 
      College, Huazhong University of Science and Technology, Wuhan, 430030, China.
FAU - Mu, Xingjiang
AU  - Mu X
AD  - Department of Pharmacology and Systems Physiology, University of Cincinnati 
      College of Medicine, Cincinnati, OH, 45267, USA.
FAU - Wang, Chenran
AU  - Wang C
AD  - Department of Cancer Biology, University of Cincinnati College of Medicine, 
      Cincinnati, OH, 45267, USA.
FAU - Peng, Tianqing
AU  - Peng T
AD  - Critical Illness Research, Lawson Health Research Institute, Ontario, Canada.
FAU - Guan, Jun-Lin
AU  - Guan JL
AD  - Department of Cancer Biology, University of Cincinnati College of Medicine, 
      Cincinnati, OH, 45267, USA.
FAU - Wang, Yigang
AU  - Wang Y
AD  - Department of Pathology and Laboratory Medicine, University of Cincinnati College 
      of Medicine, Cincinnati, OH, 45267, USA.
FAU - Jegga, Anil
AU  - Jegga A
AD  - Division of Biomedical Informatics, Cincinnati Children's Hospital Medical 
      Center, Cincinnati, OH, 45229, USA.
FAU - Huang, Kai
AU  - Huang K
AD  - Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, Hubei, 430022, China; Clinical 
      Center for Human Genomic Research, Union Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
FAU - Fan, Guo-Chang
AU  - Fan GC
AD  - Department of Pharmacology and Systems Physiology, University of Cincinnati 
      College of Medicine, Cincinnati, OH, 45267, USA. Electronic address: 
      fangg@ucmail.uc.edu.
LA  - eng
GR  - R01 GM126061/GM/NIGMS NIH HHS/United States
GR  - R01 GM132149/GM/NIGMS NIH HHS/United States
GR  - R01 NS103981/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200206
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Endosomal Sorting Complexes Required for Transport)
RN  - 0 (Keap1 protein, mouse)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Sequestosome-1 Protein)
RN  - 0 (Transcription Factors)
RN  - 0 (Tsg101 protein)
SB  - IM
MH  - Animals
MH  - *Autophagy
MH  - DNA-Binding Proteins
MH  - Endosomal Sorting Complexes Required for Transport
MH  - Kelch-Like ECH-Associated Protein 1/genetics/metabolism
MH  - Mice
MH  - *NF-E2-Related Factor 2/genetics/metabolism
MH  - Oxidative Stress
MH  - Sequestosome-1 Protein/metabolism
MH  - Transcription Factors
PMC - PMC7264471
OTO - NOTNLM
OT  - Cardiac autophagy
OT  - Myocardial ischemia-reperfusion
OT  - Nrf2
OT  - Oxidative stress
OT  - Tsg101
OT  - p62 aggregation
COIS- Declaration of competing interest None.
EDAT- 2020/02/15 06:00
MHDA- 2021/06/22 06:00
PMCR- 2020/02/06
CRDT- 2020/02/15 06:00
PHST- 2020/01/02 00:00 [received]
PHST- 2020/02/01 00:00 [revised]
PHST- 2020/02/05 00:00 [accepted]
PHST- 2020/02/15 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2020/02/15 06:00 [entrez]
PHST- 2020/02/06 00:00 [pmc-release]
AID - S2213-2317(20)30002-1 [pii]
AID - 101453 [pii]
AID - 10.1016/j.redox.2020.101453 [doi]
PST - ppublish
SO  - Redox Biol. 2020 May;32:101453. doi: 10.1016/j.redox.2020.101453. Epub 2020 Feb 
      6.